DESCRIPTION (Applicant's Abstract): The formation of scars within the lungs (pulmonary fibrosis) frequently leads to shortness of breath, disability and even death. The clinical outcome for the vast majority of patients with idiopathic pulmonary fibrosis (IPF) remains poor. It is likely that identification of specific disease mechanisms at the molecular level will provide the best avenue for development of novel therapies. One of the key cytokines in lung fibrosis is transforming growth factor beta 1 (TGF-beta1). TGF-beta1 expression is upregulated in several models of fibroproliferative lung disease. We propose that TGF-beta1's stimulatory effect on interstitial matrix accumulation is mediated through a novel cytokine, connective tissue growth factor (CTGF). CTGF is a newly described peptide that shares several profibrogenic activities with TGF-beta1, namely as a promoter of collagen and fibronectin synthesis, as a mitogen for mesenchymal cells, and as an inducer of cell adhesion. A recent investigation has shown that the CTGF gene promoter contains a TGF-beta1 response element. We have found that CTGF upregulates lung fibroblast alpha 1 type I collagen expression in vitro and that CTGF expression is upregulated during the development of fibrosis in the two animal models of lung fibrosis that we have studied. Our recent manuscript is the sentinel description of CTGF expression during lung fibrogenesis. The overall goal in this proposal is to directly test the hypothesis that: Connective tissue growth factor is a prominent regulator of collagen deposition in fibrotic lung disease. To test our hypothesis we will demonstrate the effect of recombinant CTGF on several key facets of type I collagen synthesis and degradation in vitro. We will determine, using CTGF transgenic mice and a CTGF adenoviral vector, whether overexpression of CTGF within the lung results in pulmonary fibrosis, both alone and in the presence of other fibrogenic cytokines. We will also employ the novel approach of using a hammerhead ribozyme in vitro and in vivo to study the effect of inhibiting CTGF synthesis on TGF-beta-mediated collagen synthesis and degradation. These studies will establish the role that CTGF plays in lung fibrogenesis.